Based on current evidence, severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection can result in a range of pathologies with varying degrees of intensity – from asymptomatic patients to those who suffer from fatal respiratory or multiple organ failure (Files et al.). This has raised questions among researchers about how the immune system responds to COVID-19 and why this response differs. This article aims to summarise these findings and provide a prediction on what we might expect in 2021.

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SARS-CoV-2 is a membrane-enveloped virus particle that contains an mRNA-based genome (Figure 1). The spike glycoprotein trimer (S) on the surface of the virus is responsible for viral entry by attaching to host cell angiotensin-converting enzyme 2 (ACE2) receptors. These receptors are found in abundance on the surface of cells that line the upper and lower respiratory tract (Sokolowska et al.; Xu et al.; Toor et al.). Upon entry, the virus replicates and releases more virus particles into the body, alerting the immune system to the presence of a foreign entity. The S protein and nucleoprotein (N) are both crucial targets of the immune response.

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Figure 1: The SARS-CoV-2 virus particle consisting of a membrane envelope and four proteins protecting an mRNA-based genome (Image courtesy of ViralZone, SIB Swiss Institute of Bioinformatics).

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During early infection, viral entry into cells triggers an innate immune response characterised by the production of interferon type I (IFN-α and -β), interferon type III, and proinflammatory cytokines. However, while IFNs are essential for activating different downstream innate and adaptive responses, COVID-19 patients often exhibit a weak IFN response. This impairment, together with a continued increase in proinflammatory cytokines and viral load, may result in excessive inflammation and worsening disease (Sokolowska et al.; Dan et al.; Rodrigues et al.). In severe cases, the uncontrolled and excessive release of cytokines, known as a cytokine storm, can cause multiple organ failure and death (Xiao et al.).

 

The infection site at the lungs also sees the inward migration of neutrophils and macrophages. The neutrophils release neutrophil extracellular traps (NETs) that ensnare pathogens. The infiltration of these immune cells into the lungs in severe COVID-19 cases results in a cytokine storm (Hu et al.). NETs have also been linked to acute respiratory distress syndrome (ARDS) by contributing to cytokine release (Sokolowska et al.).

 

While the innate immune response is often not sophisticated enough to ensure complete eradication of the SARS-CoV-2, the body deploys the adaptive arm of the immune system characterised by a cellular and humoral response. The transition between the innate and adaptive responses is critical in determining disease outcomes as often this is the start of immune dysregulation (Toor et al.).

 

During viral infections, the cellular response is responsible for destroying infected cells (by means of cytotoxic CD8+ T cells) and initiating the humoral response (primarily via CD4+ T helper cells). In COVID-19 patients, however, T cell levels often fall below the baseline, and it is not uncommon for patients to have lymphopenia, particularly those with acute infections (Sokolowska et al.; Files et al.). Lymphopenia and T cell exhaustion is thought to be a major cause of deteriorating clinical outcomes. Concomitantly strong T cell responses against SARS-CoV-2 are associated with reduced disease (Dan et al.; Toor et al.).

 

The humoral immune response is tasked with producing antibodies against pathogens and is critical for the success of vaccines. This response does successfully produce a variety of neutralising antibodies (nAbs) against the S and N proteins of SARS-CoV-2 that prevent reinfection (Weisberg et al.). These antibodies can be detected 4-8 days after the onset of symptoms (Wu et al.). Mucosal IgM antibodies are the first to be produced and are thought to prevent reinfection. Thereafter circulating IgA antibodies are produced, which are responsible for systemic neutralisation of the virus and lower inflammation during active infection. Finally, neutralising IgG antibodies for the S protein are produced (10-18 days after onset of symptoms). The extent and quality of these IgG nAbs is crucial for determining disease outcome (Sokolowska et al.).

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In patients that are mildly symptomatic, the response of the immune system is controlled. Upon viral entry, the inflammation that is generated attracts T cells that work to target infected cells before the virus is capable of spreading. In addition, nAbs block the virus and attract macrophages that clear infected cells. Following this, necrotic cell debris is removed via phagocytosis (Wastnedge et al.). Both the S and N proteins of SARS-CoV-2 generate antibodies. However, the S protein is currently the most promising target for vaccines as it generates the strongest nAbs (Weisberg et al.; Legros et al.).

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Disease severity correlates with nAb levels and anti-S IgG titres, and severely symptomatic patients often have high nAb levels and anti-S IgG titres. Despite high nAbs titres being associated with viral clearance in most viral infections, with SARS-CoV-2, this does not confer protection against COVID-19 progression (Legros et al.; Dan et al.; Lau et al.; Guthmiller et al.).

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The antibody response against infection with SARS-CoV-2 has unfortunately been found to be relatively short-lived, with direct implications for vaccine development and reinfection. Models have predicted protection lasting for between 4-12 months. This is similar to other common coronavirus infections. Some suggest that the speed at which the SARS-CoV-2 infection peaks may hasten the antibody response, resulting in plasma cells (i.e. those that produce antibodies) not spending sufficient time maturing in germinal centres. This translates to an antibody response that is more short-lived (Sokolowska et al.; Dan et al.; Lau et al.; Choe et al.). While nAbs may become undetectable with time, it is thought that the established immune memory does provide protection against severe disease upon re-exposure (Lau et al.). It has been reported based on recent animal studies that low nAb titres correlate with the ability to be reinfected by heterologous strains of SARS-CoV-2 (Kim et al.; Lau et al.). When considering that the antibody response in humans correlates with COVID-19 severity, these findings by Kim et al. imply that reinfection of individuals is possible especially in those who display only mild symptoms, placing them at higher risk (especially since novel variants of SARS-CoV-2 are being reported globally)(Guthmiller et al.).

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Of concern are recent variants that are reported to be more contagious. A recent study from South Africa has identified a variant capable of complete escape from therapeutic monoclonal antibodies as well as plasma from convalescent patients. Therefore, this variant is antigenically distinct and may reduce the efficacy of current S-protein-based vaccines (Wibmer et al.).

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In light of the challenges that we face with COVID-19, it is unlikely that current strategies will contain the spread of the virus in 2021 since there is no effective therapeutic treatment, and herd immunity will take time to establish (Xu et al.). We are likely to see continued waves of infections while the vaccine campaign progresses. In the future, it is possible that the emergence of less virulent variants with greater transmissibility will be observed, eventually mirroring the seasonal influenza outbreaks.

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References

• Choe, Pyoeng Gyun, et al. “Waning Antibody Responses in Asymptomatic and Symptomatic SARS-CoV-2 Infection.” Emerging Infectious Diseases, vol. 27, no. 1, Centers for Disease Control and Prevention, 2021, p. 327.

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• Dan, Jennifer M., et al. “Immunological Memory to SARS-CoV-2 Assessed for up to 8 Months after Infection.” Science, American Association for the Advancement of Science, 2021.

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• Files, Jacob K., et al. “Sustained Cellular Immune Dysregulation in Individuals Recovering from SARS-CoV-2 Infection.” The Journal of Clinical Investigation, vol. 131, no. 1, Am Soc Clin Investig, 2021.

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• Guthmiller, Jenna J., et al. “SARS-CoV-2 Infection Severity Is Linked to Superior Humoral Immunity against the Spike.” Mbio, vol. 12, no. 1, Am Soc Microbiol, 2021.

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• Hu, Biying, et al. “The Cytokine Storm and COVID-19.” Journal of Medical Virology, vol. 93, no. 1, Wiley Online Library, 2021, pp. 250–56.

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• Kim, Young-Il, et al. “Critical Role of Neutralizing Antibody for SARS-CoV-2 Reinfection and Transmission.” Emerging Microbes & Infections, Taylor & Francis, 2021, pp. 1–28.

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• Lau, Eric HY, et al. “Neutralizing Antibody Titres in SARS-CoV-2 Infections.” Nature Communications, vol. 12, no. 1, Nature Publishing Group, 2021, pp. 1–7.

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• Legros, Vincent, et al. “A Longitudinal Study of SARS-CoV-2-Infected Patients Reveals a High Correlation between Neutralizing Antibodies and COVID-19 Severity.” Cellular & Molecular Immunology, Nature Publishing Group, 2021, pp. 1–10.

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• Rodrigues, Tamara S., et al. “Inflammasomes Are Activated in Response to SARS-CoV-2 Infection and Are Associated with COVID-19 Severity in Patients.” Journal of Experimental Medicine, vol. 218, no. 3, The Rockefeller University Press, 2021.

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• Sokolowska, Milena, et al. “Immunology of COVID-19: Mechanisms, Clinical Outcome, Diagnostics, and Perspectives—A Report of the European Academy of Allergy and Clinical Immunology (EAACI).” Allergy, vol. 75, no. 10, Wiley Online Library, 2020, pp. 2445–76.

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• Toor, Salman M., et al. “T-Cell Responses and Therapies against SARS-CoV-2 Infection.” Immunology, vol. 162, no. 1, Wiley Online Library, 2021, pp. 30–43.

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• Wastnedge, Elizabeth AN, et al. “Pregnancy and COVID-19.” Physiological Reviews, vol. 101, no. 1, American Physiological Society Bethesda, MD, 2021, pp. 303–18.

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• Weisberg, Stuart P., et al. “Distinct Antibody Responses to SARS-CoV-2 in Children and Adults across the COVID-19 Clinical Spectrum.” Nature Immunology, vol. 22, no. 1, Nature Publishing Group, 2021, pp. 25–31.

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• Wibmer, Constantinos Kurt, et al. “SARS-CoV-2 501Y.V2 Escapes Neutralization by South African COVID-19 Donor Plasma.” BioRxiv, Cold Spring Harbor Laboratory, 2021, doi:10.1101/2021.01.18.427166.

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• Wu, Fan, et al. Neutralizing Antibody Responses to SARS-CoV-2 in a COVID-19 Recovered Patient Cohort and Their Implications. 2020.

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• Xiao, Fan, et al. “The Immune Dysregulations in COVID-19: Implications for the Management of Rheumatic Diseases.” Modern Rheumatology, Taylor & Francis, 2021, pp. 1–11.

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• Xu, Cong, et al. “Conformational Dynamics of SARS-CoV-2 Trimeric Spike Glycoprotein in Complex with Receptor ACE2 Revealed by Cryo-EM.” Science Advances, vol. 7, no. 1, American Association for the Advancement of Science, 2021, p. eabe5575.